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PubMed1996

Endogenous retinoic acid signaling colocalizes with advanced expression of the adult smooth muscle myosin heavy chain isoform during development of the ductus arteriosus.

During fetal development, a specialized vessel the ductus arteriosus, shunts blood from the pulmonary artery to the aorta, thus bypassing the lungs. The ductus differs primarily from the great vessels in that it is a muscular rather than an elastic artery, and the etiology of this differential development remains controversial. We present evidence that retinoic acid (RA) may contribute to the unique muscle phenotype of the ductus arteriosus. Using a transgenic mouse carrying an RA response element-lacZ transgene that expresses beta-galactosidase (beta-gal) in response to endogenous RA signals during embryonic and fetal development, we observe a strong beta-gal signal in the ductus arteriosus. By immunofluorescence, this signal colocalizes with the expression of the adult-specific smooth muscle myosin heavy chain isoform, SM2. The beta-gal signal is present throughout fetal development and persists in the neonate until the ductus arteriosus is completely closed. beta-Gal-positive cells are first detected by immunofluorescence at 13.5 days postcoitum (dpc) in the mesenchyme surrounding the ductus. By 15.5 dpc, very intense beta-gal staining localizes to the ductus arteriosus but is absent or minimal in the pulmonary trunk and aortic arch; by 17.5 dpc, the smooth muscle layers of the tunica media in the ductus arteriosus exhibit positive beta-gal staining. Immunostaining with antibodies against smooth muscle myosins shows that, while SM1 is expressed in all embryonic vessels, SM2 is precociously expressed in the ductus arteriosus. Furthermore, SM2 expression can be detected in the ductus as early as 15.5 dpc. In the neonate, the beta-gal signal persists in the smooth muscle layer of the ductus and immunostaining colocalizes with SM2 expression. These data suggest that RA may play a role in inducing and maintaining smooth muscle differentiation in the developing ductus arteriosus and may promote precocious expression of the adult vascular phenotype.

Animals↗
PubMed1990

Expression of the myc proto-oncogenes in developing human fetal brain.

We have analysed c-myc, N-myc and L-myc gene expression in developing human fetal brain by Northern hybridization, RNAase protection and in situ hybridization. The unique zonal organization of the developing fetal brain allows a particularly good assessment of the coupling of myc gene expression to cell proliferation and differentiation in vivo. By Northern and in situ hybridization, L-myc as well as c-myc and N-myc transcripts in the brain were found in the post-mitotic cortical and intermediate layers, as well as in the mitotically active layers containing the neuroepithelial precursor cells. Consistent results were also obtained for L-myc using RNAase protection analysis. Both the 3.6 and 3.8kb forms of the L-myc mRNA, resulting from alternative splicing of intron I, were detected in layers of neuroectodermal origin, but not in the meninges or choroid plexus. We also extended L-myc expression and splicing analyses to other developing human fetal tissues. L-myc mRNA was expressed in several other fetal tissues, particularly in fetal skin. Predominantly intron I containing L-myc mRNA was observed in fetal striated and cardiac muscle. Thus, L-myc is expressed in a wider spectrum of developing tissues than previously known. Our findings also, show that L-myc as well as N-myc and c-myc expression is uncoupled from cell division in developing brain.

Blotting, Northern↗
PubMed1980

Hormonal influences during fetal lung development.

Maturation of the fetal lung is accelerated by in utero treatment with corticosteroids and thyroid hormones. Other agents such as catecholamines, thyrotropin-releasing hormone, oestradiol, heroin and cyclic AMP also influence pulmonary phospholipid metabolism. Glucocorticoids cause precocious development of both lung morphology and the surfactant system in type II cells, resulting in more stable lungs with increased air space. The properties of glucocorticoid action are consistent with enzyme induction mediated by interaction of steroid with cytoplasmic glucocorticoid receptors. Receptors are present in lung of many species, including the human fetus, and in both pulmonary fibroblasts and type II cells. Corticosteroid therapy of women in premature labour is currently used to reduce the incidence of infant respiratory distress syndrome (RDS). Treatment of the mother with 12 mg betamethasone causes an approximately four-fold maximal increase in unbound glucocorticoid activity in fetal plasma which is calculated to cause 80% nuclear occupancy by receptor-steroid complex. It is likely that endogenous corticoids influence normal lung development; possible sources of cortisol include the fetal adrenal, maternal adrenal, and conversion of cortisone to cortisol by amniotic membranes and lung fibroblasts. Thyroid hormones have effects similar to corticosteroids, but appear to influence different biochemical steps. Synthetic analogues of triiodothyronine (T3) are available which readily cross the placenta, in contrast to T3 and thyroxine, and accelerate surfactant synthesis and release. Thyroid hormones probably act through nuclear receptors which are present in lung of both animals and the human. Thyroid treatment in utero also appears to accelerate lung maturation and prevent RDS in premature infants.

Animals↗
PubMed2000

Factors affecting newborn bone mineral content: in utero effects on newborn bone mineralization.

Several factors have been found recently to have a significant impact on newborn bone mineral content (BMC) and developing fetal bone. Recently we showed that maternal vitamin D deficiency may affect fetal bone mineralization. Korean winter-born newborn infants had extremely low serum 25-hydroxyvitamin D (25-OHD), high serum cross-linked carboxy-terminal telopeptide of type I collagen (ICTP; a bone resorption marker), and markedly lower (8 %) total body BMC than summer-born newborn infants. Infant total body BMC was positively correlated with cord serum 25-OHD and inversely correlated with ICTP, which was also negatively correlated with vitamin D status. In three separate studies on North American neonates we found markedly lower (8-12 %) BMC in summer newborn infants compared with winter newborn infants, the opposite of the findings for Korean neonates. The major reason for the conflicting BMC results might be the markedly different maternal vitamin D status of the North American and Korean subjects. Recently, we found evidence of decreased bone formation rates in infants who were small-for-gestational age (SGA) compared with infants who were appropriate-for-gestational age; we reported reduced BMC, cord serum osteocalcin (a marker of bone formation) and 1,25-dihydroxyvitamin D (the active metabolite of vitamin D), but no alterations in indices of fetal bone collagen metabolism. In theory, reduced utero-placental blood flow in SGA infants may result in reduced transplacental mineral supply and reduced fetal bone formation. Infants of diabetic mothers (IDM) have low BMC at birth, and infant BMC correlated inversely with poor control of diabetes in the mother, specifically first trimester maternal mean capillary blood glucose concentration, implying that factors early in pregnancy might have an effect on fetal BMC. The low BMC in IDM may be related to the decreased transplacental mineral transfer. Cord serum ICTP concentrations were higher in IDM than in control subjects, implying increased intrauterine bone resorption. BMC is consistently increased with increasing body weight and length in infants. Race and gender differences in BMC appear in early life, but not at birth. Ethanol consumption and smoking by the mother during pregnancy affect fetal skeletal development.

Animals↗
PubMed1986

Some observations on dermis development in fetal porcine skin.

The study describes dermis development in fetal porcine skin between 40 d GA and birth. The first fibroblast arrangement occurs about 47 d GA, while between 60-65 d GA the first fibres are visible. They can be identified as collagen about 67 d GA, somewhat later the dermis shows 2 strata. At the end of median gestional life, the first birefringent lattice pattern of collagen fibre bundles is formed. The first elastic fibres cannot be demonstrated before 100 d GA.A clear increase in fibrocyte numbers occurs about 70-80 d GA, the next one at birth. The thickness development of the fetal porcine dermis is closely correlated with the increase in body weight. Additionally RNA and glycogen content developments have been studied in the fetal dermis.

Animals↗
PubMed1996

Bronchial ligation enhances murine fetal lung development in whole-organ culture.

Evidence exists from both congenital anomalies and animal models that normal fetal lung development is dependent on maintenance of fluid pressure within the developing "airways." Fetal tracheostomy, allowing free egress of airway fluids, results in lung hypoplasia, indicating that some airway distending pressure is required for normal lung development to occur. In contrast, fetal tracheal ligation, which increases fetal airway pressure, reverses lung hypoplasia in animal models. The authors' experiments test the hypothesis that large airway obstruction accelerates the development of murine lungs in vitro in whole-organ culture. Fetuses from time-dated pregnant CD-1 mice at day 14 of gestation were removed (term, 20 days), and the lungs were excised. The left bronchus of each lung was ligated (n = 26), after which the left lung was isolated and cultured at 37 degrees C (95% air, 5% CO2) in BGJb media supplemented with vitamin C and antibiotics. Some fetal lungs were cultured under similar conditions without bronchial ligation (n = 11). After 7 days in culture, the lungs were taken for various analyses. The lungs were fixed in either formaldehyde and processed for paraffin embedding for light microscopic evaluation and morphometric data collection, or were freshly minced and aliquots taken for total protein and DNA content. Several more ligated and unligated lungs were processed for ultrastructural analysis. Morphometric analysis on transverse sections of lungs showed significant differences in the lung tissue size, thickness, epithelial cell height, luminal areas, perimeters, and total number of airspaces (airway + primordial alveolar airspaces). It was evident that bronchial ligation promoted lung development. The ligated lungs displayed thinning of the primordial alveolar walls with cuboidal epithelial cells. The total number of airspaces per field was lower for better developed ligated lungs because of the increased area of airspaces compared with that of the unligated lungs. The dorsoventral tissue thickness (in micrometers) of the ligated lungs was significantly greater than that of the unligated lungs (124.1 +/- 7.0 v 89.6 +/- 8.0); the average outer perimeter of the primordial alveolar airspaces was greater for ligated lungs (404.56 +/- 19.0 microns v 256.85 +/- 17.0 microns). Similarly, the luminal diameter of the spaces of ligated lungs was almost double that of the unligated lungs (38.0 +/- 2.0 microns v 20.3 +/- 2.0 microns), as was the luminal surface area. The morphometric data, which suggest enhanced maturation of the ligated lungs, are supported by results of ultrastructural studies. Ligated lungs had significantly more lamellar bodies. Although total protein and DNA content were greater among the ligated lungs, the protein/DNA ratios did not differ among the groups. The intraluminal pressure (airway pressure) of ligated lungs was 2.9 mm Hg and 3.1 mm Hg at 2 and 4 days in organ culture; the respective pressures for unligated lungs were 1.0 mm Hg and 0.8 mm Hg. These data support the hypothesis that mechanical distending pressure resulting from airway obstruction not only improves pulmonary architecture but also accelerates lung development in vitro. Although these effects have been seen in in vivo models, this is the first proposed in vitro organ culture model. This model may prove to be a powerful tool for the study of molecular mechanisms of mammalian lung development with respect to mechanical and chemical (cytokines, hormones) stimuli.

Airway Obstruction↗
PubMed1981

A morphologic and morphometric analysis of fetal lung development in the sheep.

In the sheep, fetal lung development proceeds to a later stage of maturity than in smaller laboratory animals. Of the four stages in pulmonary development recognizable in this species - embryologic, pseudoglandular, canalicular, and aveolar - the latter three are described in the present study using histologic, morphometric, and ultrastructural techniques. During the pseudoglandular stage, the major airways developed centrifugally. Cartilaginous, glandular, muscular, vascular, and neural elements were present in major airway walls from an early age. During the canalicular stage, volume expansion of the lung was accomplished by rapid growth of large terminal spaces. In the final stage, alveoli were formed following subdivision of the large terminal spaces by alveolar crests. The alveolar lining epithelium differentiated during the latter two stages producing a large increase in alveolar surface area, particularly during the alveolar stage; a large increase in pulmonary capillary surface area also accompanied alveolar development. Thus, just prior to birth, the fetal sheep lung has a well-developed air-way system and alveolar network, in preparation for postnatal gas exchange.

Animals↗
PubMed1981

Endocrine balance as a factor in the etiology of the fetal alcohol syndrome.

It is well documented that children with the fetal alcohol syndrome are a direct consequence of heavy maternal ethanol consumption during pregnancy. The mechanism by which ethanol exerts its teratogenic effect is however, far from understood. Recent experimental evidence has shown alcohol to have a direct inhibitory effect on embryogenesis. Little information, however, is available concerning other factors associated with maternal drinking which may contribute to abnormal fetal development. Proper materno-fetal hormonal balance is essential to insure successful pregnancy outcome. Of particular importance with respect to normal fetal development, are the levels of placental tropic hormones; pituitary hormones such as prolactin and oxytocin; adrenal cortical hormones; both maternal and fetal thyroid hormones; maternal and fetal sex hormones; and maternal insulin. Ethanol alters the levels of a variety of hormones associated with the hypothalamic/pituitary-gonadal, -adrenal and -thyroid axes. Many of these alterations have been observed in the male, however, with little data available on the female. In spite of the known adverse effect of ethanol on certain aspects of female reproductive function, few if any studies have examined the effects of alcohol ingestion during pregnancy on maternal endocrine balance. It is hoped that the present review will provide a rationale for the examination of alcohol effects on maternal endocrine hormones, as well as to provide possible target areas with respect to fetal development subsequent to ethanol-induced endocrine imbalance.

Alcoholic Beverages↗
PubMed2004

Prenatal growth and development of the modern human labyrinth.

The modern human bony labyrinth is morphologically distinct from that of all other primates, showing derived features linked with vestibular function and the overall shape of the cranial base. However, little is known of how this unique morphology emerges prenatally. This study examines in detail the developing fetal human labyrinth, both to document this basic aspect of cranial biology, and more specifically, to gain insight into the ontogenetic basis of its phylogenetically derived morphology. Forty-one post-mortem human fetuses, ranging from 9 to 29 weeks gestation, were investigated with high-resolution magnetic resonance imaging. Quantitative analyses of the labyrinthine morphology revealed a number of interesting age-related trends. In addition, our findings show that: (1) the prenatal labyrinth attains an adult equivalent size between 17 and 19 weeks gestation; (2) within the period investigated, shape changes to all or most of the labyrinth cease after the 17-19-week size maturation point or after the otic capsule ossifies; (3) fetal cochlea development correlates with the surrounding petrosal morphology, but not with the midline basicranium; (4) gestational age-related rotations of the ampullae and cochlea relative to the lateral canal, and posterior canal torsion are similar to documented phylogenetic trends whereas other trends remain distinct. Findings are discussed in terms of the ontogenetic processes and mechanisms that most likely led, in part, to the emergence of the phylogenetically derived adult modern human labyrinth.

Cochlea↗
PubMed1998

The human thymus. A chimeric organ comprised of central and peripheral lymphoid components.

The human thymus is a lymphoepithelial organ in which T cells develop during fetal life. After maturation and selection in the fetal thymic microenvironment, T cells emigrate to peripheral lymphoid tissues such as the spleen, gut, and lymph nodes, and establish the peripheral T cell repertoire. Although the thymus has enormous regenerative capacity during fetal development, the regenerative capacity of the human postnatal thymus decreases over time. With the advent of intensive chemotherapy regimens for a variety of cancer syndromes, and the discovery that infection with the Human Immunodeficiency Virus (HIV) leads to severe loss of CD4+ T cells, has come the need to understand the role of the human thymus in reconstitution of the immune system in adults. During a recent study of the thymus in HIV infection, we observed many CD8+ T cells in AIDS thymuses that had markers consistent with those of mature effector cytotoxic T cells usually found in peripheral immune tissues, and noted these CD8+ effector T cells were predominately located in a thymic zone termed the thymic perivascular space. This article reviews our own work on the thymus in HIV-1 infection, and discusses the work of others that, taken together, suggest that the thymus contains peripheral immune cell components not only in the setting of HIV infection, but also in myasthenia gravis, as well as throughout normal life during the process of thymus involution. Thus, the human thymus can be thought of as a chimeric organ comprised of both central and peripheral lymphoid tissues. These observations have led us to postulate that the thymic epithelial atrophy and decrease in thymopoiesis that occurs in myasthenia gravis, HIV-1 infection, and thymic involution may in part derive from cytokines or other factors produced by peripheral immune cells within the thymic perivascular space.

Adult↗
PubMed2004

Cellular composition of pancreas-associated lymphoid tissue during human fetal pancreatic development.

AIM: To study human fetal pancreatic tissue between 15 weeks of gestation and term, analysing the development of pancreatic lymphoid tissue and focusing on the presence and maturational status of dendritic cells (DCs). During normal human fetal pancreatic development lymphoid tissue arises in and around the pancreas. DCs are antigen-presenting cells which are capable of initiating immunity, but are also essential in inducing and maintaining T-cell tolerance. METHODS AND RESULTS: First, the presence and general composition of intra- and peripancreatic lymphoid tissue was investigated by histology and immunohistochemistry with antibodies to CD3, CD4, CD8, CD14, CD20, CD68, and CD79. Intrapancreatic lymphoid tissue (IPLT) appeared to be present only from 29 weeks of gestation onwards, and had a similar composition to peripancreatic lymphoid tissue (PPLT), which was found in all 23 specimens examined. Both forms of lymphoid tissue had an architecture similar to lymph nodes, with separate B- and T-lymphocyte areas and scattered macrophages. DCs were investigated in detail by immunohistochemistry for CD1a, CD83, CD86, CD123, Langerin, and DC-LAMP. Both Langerin, a marker for immature DCs, as well as DC-LAMP, a marker for mature DCs, were expressed by cells in both the IPLT and PPLT at all ages examined. CONCLUSION: The presence of DCs at all developmental stages, expressing various maturation-related markers, in addition to the general composition of the human fetal PPLT and IPLT suggests that this is fully functional and has a function comparable to peripheral lymph nodes.

Antigens, CD↗
PubMed1994

Fetal hematopoietic alterations after maternal exposure to ethylene glycol monomethyl ether: prolymphoid cell targeting.

Ethylene glycol monomethyl ether (EGME), which is extensively used in the chemical industries, has been associated with hematologic disorders in both humans and experimental animals. EGME is metabolized to the active compound methoxy-acetic acid (MAA), which readily crosses the placenta and impairs fetal development. However, little is known about the effect of maternal EGME exposure on the development of fetal immunity. In the present report, in utero treatment with EGME was found to alter expression of murine thymocyte and liver fetal cell-surface markers. Pregnant mice were exposed to 100, 150, or 200 mg/kg EGME from gestational days (gd) 10 to 17 and offspring examined on gd 18. Significant thymic atrophy and cellular depletion were found in EGME-exposed fetal mice. Flow cytometric analysis indicated that EGME treatment resulted in decreased percentages of CD4+8+ thymocytes and increased percentages of CD4-8- thymocytes. In vitro exposure to MAA did not result in decreased thymocyte viability or proliferation. These data suggest that EGME, in addition to producing thymic hypocellularity, may inhibit thymocyte maturation. EGME also reduced the percentage of CD45+ leukocytic cells present in fetal liver, an alteration that appeared to be largely manifested by decreased numbers of CD45R+ and CD44dim prolymphoid cells. In vitro MAA exposure of fetal liver cells enriched for lymphoid precursors resulted in significant inhibition of proliferation. Reconstitution of irradiated hosts with gd 18 fetal liver cells from vehicle and EGME-exposed syngeneic donors demonstrated impaired ability of the EGME-treated fetal liver to repopulate the host spleen with B or T lymphocytes. These data suggest that EGME-induced immunosuppression may result from targeting of multiple hematopoietic compartments. Further, the present data indicate that fetal liver prolymphocytes may represent sensitive targets of EGME exposure.

Acetates↗
PubMed1994

Thinness at birth and insulin resistance in adult life.

Type 2 (non-insulin-dependent) diabetes mellitus may originate through impaired development in fetal life. Both insulin deficiency and resistance to the action of insulin are thought to be important in its pathogenesis. Although there is evidence that impaired fetal development may result in insulin deficiency, it is not known whether insulin resistance could also be a consequence of reduced early growth. Insulin resistance was therefore measured in 81 normoglycaemic subjects, and 22 subjects with impaired glucose tolerance, who were born in Preston, UK, between 1935 and 1943. Their birth measurements had been recorded in detail. Insulin resistance was measured by the insulin tolerance test which uses the rate of fall in blood glucose concentrations after intravenous injection of insulin as an index of insulin resistance. Men and women who were thin at birth, as measured by a low ponderal index, were more insulin resistant. The association was statistically significant (p = 0.01) and independent of duration of gestation, adult body mass index and waist to hip ratio and of confounding variables including social class at birth or currently. Thinness at birth and in adult life has opposing effects such that resistance fell with increasing ponderal index at birth but rose with increasing adult body mass index. It is concluded that insulin resistance is associated with impaired development in fetal life.

Adult↗
PubMed1986

Persisting subsensitivity of the striatal dopamine system after fetal exposure to beta-endorphin.

Fetal exposure of rats to beta-endorphin during the third trimester, either alone or with alpha-MSH, resulted in mild developmental delay and significant decreases in striatal dopamine receptor density (subsensitivity) persisting through maturity. The apparent paradoxical down-regulation of dopamine receptors in the presence of beta-endorphin was consistent with fetal exposure to dopamine receptor antagonists and synthesis inhibitors. These findings suggest biophysical properties of receptors which are unique to fetal development including loss of plasticity after exposure to antagonists. Permanent, down-regulation of the striatal dopamine system may be one mechanism underlying delayed development after fetal exposure to beta-endorphin which may accompany hypoxia. Even though there were no statistically significant differences between males and females in density of the dopamine receptor, the behavioral profile after peptide treatment was sexually demorphic. Behaviorally, female rats appeared sensitized to perinatal alpha-MSH and males to alpha-endorphin.

Animals↗
PubMed1999

Smooth muscle expresses bone morphogenetic protein (Vgr-1/BMP-6) in human fetal intestine.

During human fetal development, autocrine TGF-beta1 regulates the synthesis of specific collagen types by intestinal smooth muscle cells in an age-dependent manner. Vgr-1/BMP6, a member of the TGF-beta superfamily, modulates epithelial, endochondral and neural tissue development in mice: a related peptide is essential to gut morphogenesis in Drosophila. This is the first study to detect vgr-1/BMP-6 during human intestinal organogenesis. Polyclonal antibodies to the precursor and mature fragments of vgr-1 were used in immunohistochemical studies of human intestine at 15, 19 and 24 weeks' gestation. Immunoreactivity was detected with the antibody directed against the precursor portion of vgr-1. Only smooth muscle structures stained for vgr-1 including muscularis propria, muscularis mucosa and vasculature. BMP-6 mRNA was detected by RNase protection assay in cultured muscle cells from 11, 17 and 22 weeks' gestation. This study demonstrates vgr-1/BMP 6 expression in the developing human fetal intestine, exclusively in muscle.

Animals↗
PubMed1989

Hypophysectomy and porcine fetal lung development.

The effect of hypophysectomy on the development of the lung parenchyma and maturation of pulmonary alveolar type II cells was examined in the fetal pig. In fetuses from four different gilts, hypophysectomy was performed on gestational day 69 or 70. Littermates from the same gilts served as controls. Fetuses were delivered by caesarean section at term (113 +/- 1 days of gestation), and the lungs were fixed by intratracheal instillation. Plasma cortisol and thyroxine concentrations in the umbilical artery were markedly lower for hypophysectomized fetuses compared with control fetuses. Body weight was similar for both groups of fetuses. Total lung volume was 53% smaller in hypophysectomized fetuses compared with control fetuses. However, alveolar septal tissue and capillary luminal volumes were similar in both groups. Total lung alveolar surface area was twice as great in control animals compared with hypophysectomized animals. The volumes of epithelium, interstitium, and endothelium of centriacinar alveolar septa per unit surface area of epithelial basal lamina were 3.7, 4.8, and 2.4 times greater in hypophysectomized fetuses compared with control fetuses. Alveolar type II cell composition also differed significantly between groups. The volume fraction of glycogen in type II cells was 51% for hypophysectomized fetuses and 12% for control fetuses, while lamellar body volume fraction was 8% in hypophysectomized fetuses and 23% in control fetuses. The frequency of alveolar type II cell contact with mesenchymal interstitial cells via foot processes was 5 times greater in the lungs of control animals compared with hypophysectomized animals. These findings demonstrate significant effects of hypophysectomy on the morphogenetic and cytodifferentiation activities of all major tissue compartments of the pulmonary gas exchange area during the final trimester of fetal development.

Animals↗
PubMed1994

Muscarinic receptor-dependent activation of phospholipase C in the developing human fetal central nervous system.

The coupling of muscarinic-cholinergic receptors (mAChR) to adenylate cyclase and phospholipase C (PLC) second messenger systems has been demonstrated in many animal species. However, little is known about this association in the developing human central nervous system. Because of the proposed role of acetylcholine in the regulation of development and differentiation of neural cells, an understanding of these relationships during human fetal development gains importance. We report, in this communication, the coupling of mAChR with PLC in the human fetal brain. This coupling was determined using two independent approaches that relied upon estimating the accumulation of inositol phosphates (IPs) and cytidine diphosphate diacylglycerol (CDP-DAG). Carbachol treatment of brain slices, in the presence of lithium, resulted in the accumulation of IPs. Analysis of the kinetics of this accumulation showed that IP3 and IP2 increased rapidly, reaching a peak or plateau before IP. The results also showed that agonist-stimulated PLC produced two second messengers, IP3 and DAG. The production of DAG was strongly supported by the carbachol-dependent increase of CDP-DAG. The accumulation of IP and CDP-DAG was dependent on agonist concentration. The obtained EC50 values were approximately: carbachol 47 microM; acetylcholine 6 microM; and oxotremorine 25 microM. Unexpectedly, all three agonists demonstrated a similar efficacy. The cholinergic stimulation of inositide hydrolysis appears to be the result of activation of the m1 muscarinic receptor.

Atropine↗